Vindinghagan5853

As decisions in drug development increasingly rely on predictions from mechanistic systems models, assessing the predictive capability of such models is becoming more important. Several frameworks for the development of quantitative systems pharmacology (QSP) models have been proposed. In this paper, we add to this body of work with a framework that focuses on the appropriate use of qualitative and quantitative model evaluation methods. We provide details and references for those wishing to apply these methods, which include sensitivity and identifiability analyses, as well as concepts such as validation and uncertainty quantification. Many of these methods have been used successfully in other fields, but are not as common in QSP modeling. BAY-876 We illustrate how to apply these methods to evaluate QSP models, and propose methods to use in two case studies. We also share examples of misleading results when inappropriate analyses are used.

What is the central question of this study? First, we validated easy-to-use oscillometric left ventricular ejection time (LVET) against echocardiographic LVET. Second, we investigated progression of left ventricular ejection time index (LVETI), pre-ejection period index (PEPI), total electromechanical systole index (QS2I) and PEP/LVET ratio during 60 days of head-down tilt (HDT). What is the main finding and its importance? The LVET

and LVET

showed good agreement in effect direction. Hence, LVET

might be useful to evaluate cardiovascular responses during space flight. Moreover, the approach might be useful for individual follow-up of patients with altered ejection times. Furthermore, significant effects of 60days of HDT were captured by measurements of LVETI, PEPI, QS2I and PEP/LVET ratio.

Systolic time intervals that are easy to detect might be used as parameters reflecting cardiovascular deconditioning. We compared left ventricular ejection time (LVET) measured via ultrasound Doppler on the left vand r = 0.73 with P less then 0.05 on the last day of bed rest). The shortening of LVET during HDT bed rest measured with both approaches was highly concordant in their effect direction, with a concordance rate of 0.96. Our results also demonstrated a significant decrease of LVETI (P less then 0.0001) and QS2I (P = 0.0992) and a prolongation of PEPI (P = 0.0049) and PEP/LVET (P = 0.0003) during HDT bed rest over 60 days. Four days after bed rest, LVETI recovered completely to its baseline value. Owing to the relationship between shortening of LVETI and heart failure progression, the easy-to-use oscillometric method might not only be a useful way to evaluate the cardiovascular system during space flights, but could also be of high value in a clinical setting.

Red meat intake is reported to be correlated with chronic diseases. A potential causal factor is N-glycolylneuraminic acid (Neu5Gc) which metabolically incorporates into diverse glycoconjugates in humans. This study aims to investigate the impact of exposure to Neu5Gc-rich red meat on healthy cytidine-5'-monophospho-N-acetylneuraminic acid hydroxylase (Cmah) knock-out mice and the underlying mechanisms.

CMAH

mice are fed Neu5Gc-rich diet for short-term (4 months) and long-term (10 months). Health status and levels of inflammatory cytokines are assessed. Caco-2 cells are used to investigate the intestinal absorption of Neu5Gc-containing glycoprotein, and in vitro fermentation is used to investigate the Neu5Gc utilization by gut microbiota. Neu5Gc-rich diets show neither measurable abnormality in physio-biochemical and inflammatory indexes nor observable alterations of liver tissue in mice. Glycosylation of lactoferrin limits its intestinal epithelial absorption, and the absorption of Neu5Gc attach onto glycoprotein is thus limited. Neu5Gc is also simultaneously utilized by microorganisms under simulated gut conditions.

The results indicate that the long-term intake of Neu5Gc-rich red meat has no adverse effect on the health of CMAH

mice, which may be related to the limited absorption of Neu5Gc that is regulated by protein glycosylation, and the metabolism of Neu5Gc by gut microorganisms.

The results indicate that the long-term intake of Neu5Gc-rich red meat has no adverse effect on the health of CMAH-/- mice, which may be related to the limited absorption of Neu5Gc that is regulated by protein glycosylation, and the metabolism of Neu5Gc by gut microorganisms.Only the dried stigma of the saffron, a flower deemed as the most valuable spice globally, is utilized for industrial production. Hence, there exists a growing interest in utilizing saffron floral bio-residues. The anti-hyperuricemic activity of a flavonoid extract from saffron floral bio-residues was assessed in potassium oxonate-induced hyperuricemia mice. In addition, an ultra-high performance liquid chromatography-triple quadrupole mass spectrometry method was established and validated to determine the pharmacokinetics of five main flavonoids and three phase-II metabolites in rat plasma after oral administration of the flavonoid extract for the first time. Compared with pharmacokinetic parameters of kaempferol-3-O-sophoroside, the most abundant flavonoid in the extract, and its aglycone kaempferol, we observed that coexisting compounds significantly reduced the absorption, accelerated the excretion of kaempferol-3-O-sophoroside, while significantly increasing the absorption and prolonging the residence time of kaempferol in the flavonoid extract. These results suggest the promising potential of the flavonoid extract from saffron floral bio-residues as an anti-hyperuricemic agent. Kaempferol was absorbed in plasma at high concentrations owing to the biotransformation of kaempferol glycosides in vivo.

Plant disease is one of the most serious problems in agriculture that can damage crops. Chemical fungicides are widely used to control plant diseases, but have led to resistance and a series of environmental problems. It is, therefore, necessary to develop highly effective and eco-friendly antimicrobial compounds with novel structures.

A series of novel hydantoin cyclohexyl sulfonamide derivatives were synthesized through an intramolecular condensation reaction. The bioassay results indicated that a majority of the title compounds displayed potent inhibitory activity against Botrytis cinerea, Sclerotinia sclerotiorum and Erwinia carotorora. The in vivo inhibition rate of compound 3h was 91.01% against B. cinerea, which was higher than that of iprodione (84.07%). Compound 3w showed excellent antifungal activity against B. cinerea with a half-maximal effective concentration (EC

) of 4.80 μg ml

, which is lower than that of iprodione. Compound 3q had an EC

value of 1.44 μg ml

against S. sclerotiorum, which was close to that of iprodione (1.39 μg ml

), and the inhibition rate was also similar to that of iprodione. Compounds 3i and 3w had the best inhibition efficacy against S. sclerotiorum, both on growth of the mycelium and sclerotia and in the greenhouse pot test in vitro. Further study showed that compounds 3h, 3r and 3s have superb antibacterial activity against E. carotorora with EC

values of 2.65, 4.24 and 4.29 μg ml

respectively, and were superior to streptomycin sulfate (5.96 μg ml

).

Because of their excellent antifungal and antibacterial activity against B. cinerea, S. sclerotiorum and E. carotorora, these hydantoin cyclohexyl sulfonamide derivatives could be considered as suitable candidates for new antimicrobial agents.

Because of their excellent antifungal and antibacterial activity against B. cinerea, S. sclerotiorum and E. carotorora, these hydantoin cyclohexyl sulfonamide derivatives could be considered as suitable candidates for new antimicrobial agents.

To explore nurses' perceptions of the transformation in Singapore's nursing education and its impact on the delivery of nursing care.

Nursing education in Singapore has sailed through a sea of changes, from the apprenticeship model of training in hospitals to institutions of higher learning. Limited primary studies have explored the evolution of nursing education, and none have explored its impact on the delivery of nursing care, based on nurses' perceptions.

A descriptive qualitative design with purposive and snowball sampling was used to recruit 18 experienced nurses from local teaching institutions and healthcare clusters. Semistructured individual face-to-face interviews were conducted using an interview guide. Data were analysed using thematic analysis. The Consolidated Criteria for Reporting Qualitative Research reporting guideline was used to report the study.

Five themes emerged 'evolution of the nursing education approach', 'clinical learning environments', 'evaluation of changes in the nursing education approach', 'attitudes toward the provision of various levels of education' and 'influences of various competencies on the delivery of nursing care'.

Changes in teaching pedagogies, learning, assessment, curriculum structure, content and clinical learning environment were commonly reported, which provided insights into understanding nursing education transformation and its impact on nursing practice.

The findings could better prepare nurses for the demanding needs of the contemporary healthcare landscape. Nurse educators and leaders should evaluate gaps in nursing education and implement strategies to improve students' learning experiences and outcomes.

Policy-makers can draw on our findings to revise the core competencies guidelines and improve future training by supporting the healthcare needs of society.

Policy-makers can draw on our findings to revise the core competencies guidelines and improve future training by supporting the healthcare needs of society.

To describe how much of the recent increase in hospital-cardiologist integration has come from acquisitions of physician practices compared to individual employment decisions. While the role of physician practice acquisitions has received considerable attention in the news, integration may also be driven by individual physicians accepting employment at hospital-based practices.

American Medical Association Physician Masterfile and Medicare data.

Analysis of changes in hospital-cardiologist integration from 2011-2018. We measured increases in integration and changes in the number of independent and hospital-owned practices.

N/A PRINCIPAL FINDINGS 18 percent of cardiologists were integrated in 2011, rising to 25 percent in 2016. Of this rise, 48 percent occurred with no acquisitions. Physicians who had completed residencies in the past five years (early-career physicians) had higher rates of integration which also increased over time the percentage of early-career physicians joining hospital systems rose from 25 to 32 percent, indicating rapid growth in the number of physicians who began their careers working in hospital-based sites.

A large and growing portion of hospital-cardiologist integration came from hospital employment at the individual physician level. Future policies focused on preserving competition and affordability may benefit from better understanding this form of consolidation.

A large and growing portion of hospital-cardiologist integration came from hospital employment at the individual physician level. Future policies focused on preserving competition and affordability may benefit from better understanding this form of consolidation.